Safety of cyclooxygenase-2 inhibitors in osteoarthritis: outcomes of a systematic review and meta-analysis.

[en] Objective: Our aim was to assess the safety of cyclooxygenase-2 (COX-2) inhibitors in the management of osteoarthritis (OA) in a systematic review and meta-analysis of randomized, placebo-controlled trials. Methods: A comprehensive literature search was undertaken in the databases MEDLINE, Cochrane Central Register of Controlled Trials (Ovid CENTRAL) and Scopus. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with COX-2 inhibitors in patients with OA were eligible for inclusion. Two authors appraised titles, abstracts and full-text papers for suitability and then assessed the studies for random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data and selective outcomes reporting. The primary outcomes of interest were gastrointestinal disorders, cardiac disorders, vascular disorders, nervous system disorders, skin and subcutaneous tissue disorders, hepatobiliary disorders, renal and urinary disorders, as well as overall severe and serious AEs, drug-related AEs and mortality. Secondary outcomes were withdrawals due to AEs (i.e. the number of participants who stopped the treatment due to an AE) and total number of AEs (i.e. the number of patients who experienced any AE at least once). Results: Database searches identified 2149 records from which, after exclusions, 40 trials were included in the meta-analysis. The use of COX-2 inhibitors in OA was associated with a significant increased risk of drug-related AEs compared with placebo (relative risk (RR) 1.26, 95% CI 1.09–1.46; I2 = 24%). The risk of upper gastrointestinal complications (including dyspepsia, gastritis and heartburn) was significantly increased with COX-2 inhibitors versus placebo (RR 1.19, 95% CI 1.03–1.38; I2 = 0%), particularly for abdominal pain, which increased by 40% with COX-2 inhibitors (RR 1.40, 95% CI 1.08–1.80; I2 = 0%). The risk of hypertension increased by 45% overall (RR 1.45, 95% CI 1.01–2.10; I2 = 25%); however, when rofecoxib was removed from the analysis the risk of hypertension in the COX-2 inhibitor group was no longer significant (RR 1.21, 95% CI 0.80–1.83; I2 = 20%). The overall risk of heart failure and edema was increased by nearly 70% with COX-2 inhibitors versus placebo (RR 1.68, 95% CI 1.22–2.31; 0%) and this level of risk did not change appreciably when rofecoxib was excluded (RR 1.67, 95% CI 1.21–2.29; 0%). Conclusions: In our analysis, COX-2 inhibitors were associated with an increased risk of upper gastrointestinal AEs, especially abdominal pain. We also found an increased risk of cardiovascular AEs with COX-2 inhibitors, namely hypertension, heart failure and edema.

Disciplines :

Public health, health care sciences & services
General & internal medicine

Author, co-author :

Curtis, E.

Fuggle, N.

Shaw, S.

Spooner, S.

Ntani, G.

Parsons, C.

Corp, N.

Honvo, Germain ; Université de Liège - ULiège > Département des sciences de la santé publique > Epidémiologie clinique

Baird, J.

Maggi, S.

More authors (4 more)

Language :

English

Title :

Safety of cyclooxygenase-2 inhibitors in osteoarthritis: outcomes of a systematic review and meta-analysis.

Publication date :

2019

Journal title :

Drugs and Aging

ISSN :

1170-229X

eISSN :

1179-1969

Publisher :

Adis International, United Kingdom

Volume :

Issue :

suppl 1

Pages :

25-44

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 15 May 2019

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64 (5 by ULiège)

Number of downloads

1 (1 by ULiège)

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Bibliography

Harirforoosh S, Asghar W, Jamali F. Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci. 2013;16(5):821–47.
Donnelly MT, Hawkey CJ. Review article: COX-II inhibitors—a new generation of safer NSAIDs? Aliment Pharmacol Ther. 1997;11(2):227–36.
Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352(11):1092–102. 10.1056/NEJMoa050493.
Ott E, Nussmeier NA, Duke PC, Feneck RO, Alston RP, Snabes MC, et al. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2003;125(6):1481–92.
Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med. 2005;352(11):1081–91. 10.1056/NEJMoa050330.
Pillans PI, Ghiculescu RA, Lampe G, Wilson R, Wong R, Macdonald GA. Severe acute liver injury associated with lumiracoxib. J Gastroenterol Hepatol. 2012;27(6):1102–5. 10.1111/j.1440-1746.2011.07036.x.
Patrignani P, Tacconelli S, Bruno A, Sostres C, Lanas A. Managing the adverse effects of nonsteroidal anti-inflammatory drugs. Expert Rev Clin Pharmacol. 2011;4(5):605–21. 10.1586/ecp.11.36.
Yang M, Wang HT, Zhao M, Meng WB, Ou JQ, He JH, et al. Network meta-analysis comparing relatively selective COX-2 inhibitors versus coxibs for the prevention of NSAID-induced gastrointestinal injury. Medicine (Baltimore). 2015;94(40):e1592. 10.1097/MD.0000000000001592.
van Walsem A, Pandhi S, Nixon RM, Guyot P, Karabis A, Moore RA. Relative benefit-risk comparing diclofenac to other traditional non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors in patients with osteoarthritis or rheumatoid arthritis: a network meta-analysis. Arthritis Res Ther. 2015;17:66. 10.1186/s13075-015-0554-0.
Essex MN, Zhang RY, Berger MF, Upadhyay S, Park PW. Safety of celecoxib compared with placebo and non-selective NSAIDs: cumulative meta-analysis of 89 randomized controlled trials. Expert Opin Drug Saf. 2013;12(4):465–77. 10.1517/14740338.2013.780595.
Coxib and traditional NSAID Trialists’ (CNT) Collaboration, Bhala N, Emberson J, Merhi A, Abramson S, Arber N, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769–79. 10.1016/s0140-6736(13)60900-9.
Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086. 10.1136/bmj.c7086.
Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials. JAMA. 2006;296(13):1619–32. 10.1001/jama.296.13.jrv60015.
McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 2006;296(13):1633–44. 10.1001/jama.296.13.jrv60011.
Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions. Version 5.1.0 (updated March 2011). The Cochrane Collaboration. http://www.handbook.cochrane.org.
Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62(10):1006–12. 10.1016/j.jclinepi.2009.06.005.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.
Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med. 2007;26(1):53–77. 10.1002/sim.2528.
Stijnen T, Hamza TH, Ozdemir P. Random effects meta-analysis of event outcome in the framework of the generalized linear mixed model with applications in sparse data. Stat Med. 2010;29(29):3046–67. 10.1002/sim.4040.
Normand SL. Meta-analysis: formulating, evaluating, combining, and reporting. Stat Med. 1999;18(3):321–59.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60. 10.1136/bmj.327.7414.557.
Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1 Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94. 10.1016/j.jclinepi.2010.04.026.
GRADEpro GDT. GRADEpro Guideline Development Tool [Software]. McMaster University, 2015 (developed by Evidence Prime, Inc.). Evidence Prime, Inc. http://gradepro.org.
Bensen WG, Fiechtner JJ, McMillen JI, Zhao WW, Yu SS, Woods EM, et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc. 1999;74(11):1095–105. 10.4065/74.11.1095.
Bingham CO 3rd, Sebba AI, Rubin BR, Ruoff GE, Kremer J, Bird S, et al. Efficacy and safety of etoricoxib 30 mg and celecoxib 200 mg in the treatment of osteoarthritis in two identically designed, randomized, placebo-controlled, non-inferiority studies. Rheumatology (Oxford). 2007;46(3):496–507. 10.1093/rheumatology/kel296.
Cannon CP, Chen C, Curtis SP, Viscusi J, Ahmed T, Dibattiste PM. A comparison of cardiovascular biomarkers in patients treated for three months with etoricoxib, celecoxib, ibuprofen, and placebo. Arch Drug Inf. 2008;1(1):4–13. 10.1111/j.1753-5174.2007.00002.x.
Conaghan PG, Dickson J, Bolten W, Cevc G, Rother M. A multicentre, randomized, placebo- and active-controlled trial comparing the efficacy and safety of topical ketoprofen in Transfersome gel (IDEA-033) with ketoprofen-free vehicle (TDT 064) and oral celecoxib for knee pain associated with osteoarthritis. Rheumatology (Oxford). 2013;52(7):1303–12. 10.1093/rheumatology/ket133.
Cryer BL, Sostek MB, Fort JG, Svensson O, Hwang C, Hochberg MC. A fixed-dose combination of naproxen and esomeprazole magnesium has comparable upper gastrointestinal tolerability to celecoxib in patients with osteoarthritis of the knee: results from two randomized, parallel-group, placebo-controlled trials. Ann Med. 2011;43(8):594–605. 10.3109/07853890.2011.625971.
Day R, Morrison B, Luza A, Castaneda O, Strusberg A, Nahir M, et al. A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis. Rofecoxib/Ibuprofen Comparator Study Group. Arch Intern Med. 2000;160(12):1781–7.
DeLemos BP, Xiang J, Benson C, Gana TJ, Pascual ML, Rosanna R, et al. Tramadol hydrochloride extended-release once-daily in the treatment of osteoarthritis of the knee and/or hip: a double-blind, randomized, dose-ranging trial. Am J Ther. 2011;18(3):216–26. 10.1097/MJT.0b013e3181cec307.
Ehrich EW, Schnitzer TJ, McIlwain H, Levy R, Wolfe F, Weisman M, et al. Effect of specific COX-2 inhibition in osteoarthritis of the knee: a 6 week double blind, placebo controlled pilot study of rofecoxib. Rofecoxib Osteoarthritis Pilot Study Group. J Rheumatol. 1999;26(11):2438–47.
Essex MN, O’Connell M, Bhadra Brown P. Response to nonsteroidal anti-inflammatory drugs in African Americans with osteoarthritis of the knee. J Int Med Res. 2012;40(6):2251–66. 10.1177/030006051204000623.
Essex MN, Behar R, O’Connell MA, Brown PB. Efficacy and tolerability of celecoxib and naproxen versus placebo in Hispanic patients with knee osteoarthritis. Int J Gen Med. 2014;7:227–35. 10.2147/ijgm.s61297.
Essex MN, O’Connell MA, Behar R, Bao W. Efficacy and safety of nonsteroidal anti-inflammatory drugs in Asian patients with knee osteoarthritis: summary of a randomized, placebo-controlled study. Int J Rheum Dis. 2016;19(3):262–70. 10.1111/1756-185x.12667.
Fleischmann R, Sheldon E, Maldonado-Cocco J, Dutta D, Yu S, Sloan VS. Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a prospective randomized 13-week study versus placebo and celecoxib. Clin Rheumatol. 2006;25(1):42–53. 10.1007/s10067-005-1126-5.
Ghosh S, Paul S, Das N, Bhattacharyya TK. A study on the effects of diclofenac sodium and etoricoxib in the treatment of osteoarthritis. J Indian Med Assoc. 2007;105(5):260–2.
Gordo AC, Walker C, Armada B, Zhou D. Efficacy of celecoxib versus ibuprofen for the treatment of patients with osteoarthritis of the knee: a randomized double-blind, non-inferiority trial. J Int Med Res. 2017;45(1):59–74. 10.1177/0300060516673707.
Gottesdiener K, Schnitzer T, Fisher C, Bockow B, Markenson J, Ko A, et al. Results of a randomized, dose-ranging trial of etoricoxib in patients with osteoarthritis. Rheumatology (Oxford). 2002;41(9):1052–61.
Karlsson J, Pivodic A, Aguirre D, Schnitzer TJ. Efficacy, safety, and tolerability of the cyclooxygenase-inhibiting nitric oxide donator naproxcinod in treating osteoarthritis of the hip or knee. J Rheumatol. 2009;36(6):1290–7. 10.3899/jrheum.081011.
Kivitz AJ, Moskowitz RW, Woods E, Hubbard RC, Verburg KM, Lefkowith JB, et al. Comparative efficacy and safety of celecoxib and naproxen in the treatment of osteoarthritis of the hip. J Int Med Res. 2001;29(6):467–79. 10.1177/147323000102900602.
Laine L, Harper S, Simon T, Bath R, Johanson J, Schwartz H, et al. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Rofecoxib Osteoarthritis Endoscopy Study Group. Gastroenterology. 1999;117(4):776–83.
Lehmann R, Brzosko M, Kopsa P, Nischik R, Kreisse A, Thurston H, et al. Efficacy and tolerability of lumiracoxib 100 mg once daily in knee osteoarthritis: a 13-week, randomized, double-blind study vs. placebo and celecoxib. Curr Med Res Opin. 2005;21(4):517–26. 10.1185/030079905x38196.
Leung AT, Malmstrom K, Gallacher AE, Sarembock B, Poor G, Beaulieu A, et al. Efficacy and tolerability profile of etoricoxib in patients with osteoarthritis: a randomized, double-blind, placebo and active-comparator controlled 12-week efficacy trial. Curr Med Res Opin. 2002;18(2):49–58. 10.1185/030079902125000282.
McKenna F, Borenstein D, Wendt H, Wallemark C, Lefkowith JB, Geis GS. Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol. 2001;30(1):11–8.
Puopolo A, Boice JA, Fidelholtz JL, Littlejohn TW, Miranda P, Berrocal A, et al. A randomized placebo-controlled trial comparing the efficacy of etoricoxib 30 mg and ibuprofen 2400 mg for the treatment of patients with osteoarthritis. Osteoarthr Cartil. 2007;15(12):1348–56. 10.1016/j.joca.2007.05.022.
Reginster JY, Malmstrom K, Mehta A, Bergman G, Ko AT, Curtis SP, et al. Evaluation of the efficacy and safety of etoricoxib compared with naproxen in two, 138-week randomised studies of patients with osteoarthritis. Ann Rheum Dis. 2007;66(7):945–51. 10.1136/ard.2006.059162.
Rother M, Lavins BJ, Kneer W, Lehnhardt K, Seidel EJ, Mazgareanu S. Efficacy and safety of epicutaneous ketoprofen in Transfersome (IDEA-033) versus oral celecoxib and placebo in osteoarthritis of the knee: multicentre randomised controlled trial. Ann Rheum Dis. 2007;66(9):1178–83. 10.1136/ard.2006.065128.
Saag K, van der Heijde D, Fisher C, Samara A, DeTora L, Bolognese J, et al. Rofecoxib, a new cyclooxygenase 2 inhibitor, shows sustained efficacy, comparable with other nonsteroidal anti-inflammatory drugs: a 6-week and a 1-year trial in patients with osteoarthritis. Osteoarthritis Studies Group. Arch Fam Med. 2000;9(10):1124–34.
Sawitzke AD, Shi H, Finco MF, Dunlop DD, Harris CL, Singer NG, et al. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. Ann Rheum Dis. 2010;69(8):1459–64. 10.1136/ard.2009.120469.
Schnitzer TJ, Kivitz AJ, Lipetz RS, Sanders N, Hee A. Comparison of the COX-inhibiting nitric oxide donator AZD3582 and rofecoxib in treating the signs and symptoms of Osteoarthritis of the knee. Arthritis Rheumatol. 2005;53(6):827–37. 10.1002/art.21586.
Schnitzer TJ, Dattani ID, Seriolo B, Schneider H, Moore A, Tseng L, et al. A 13-week, multicenter, randomized, double-blind study of lumiracoxib in hip osteoarthritis. Clin Rheumatol. 2011;30(11):1433–46. 10.1007/s10067-011-1776-4.
Sheldon E, Beaulieu A, Paster Z, Dutta D, Yu S, Sloan VS. Efficacy and tolerability of lumiracoxib in the treatment of osteoarthritis of the knee: a 13-week, randomized, double-blind comparison with celecoxib and placebo. Clin Ther. 2005;27(1):64–77. 10.1016/j.clinthera.2005.01.002.
Smugar SS, Schnitzer TJ, Weaver AL, Rubin BR, Polis AB, Tershakovec AM. Rofecoxib 12.5 mg, rofecoxib 25 mg, and celecoxib 200 mg in the treatment of symptomatic osteoarthritis: results of two similarly designed studies. Curr Med Res Opin. 2006;22(7):1353–67. 10.1185/030079906x104876.
Tannenbaum H, Berenbaum F, Reginster JY, Zacher J, Robinson J, Poor G, et al. Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a 13 week, randomised, double blind study versus placebo and celecoxib. Ann Rheum Dis. 2004;63(11):1419–26. 10.1136/ard.2003.015974.
Truitt KE, Sperling RS, Ettinger WH Jr, Greenwald M, DeTora L, Zeng Q, et al. A multicenter, randomized, controlled trial to evaluate the safety profile, tolerability, and efficacy of rofecoxib in advanced elderly patients with osteoarthritis. Aging (Milano). 2001;13(2):112–21.
Weaver AL, Messner RP, Storms WW, Polis AB, Najarian DK, Petruschke RA, et al. Treatment of patients with osteoarthritis with rofecoxib compared with nabumetone. J Clin Rheumatol. 2006;12(1):17–25. 10.1097/01.rhu.0000200384.79405.33.
Wiesenhutter CW, Boice JA, Ko A, Sheldon EA, Murphy FT, Wittmer BA, et al. Evaluation of the comparative efficacy of etoricoxib and ibuprofen for treatment of patients with osteoarthritis: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. 2005;80(4):470–9.
Williams GW, Ettlinger RE, Ruderman EM, Hubbard RC, Lonien ME, Yu SS, et al. Treatment of osteoarthritis with a once-daily dosing regimen of celecoxib: a randomized, controlled trial. J Clin Rheumatol. 2000;6(2):65–74.
Mallen SR, Essex MN, Zhang R. Gastrointestinal tolerability of NSAIDs in elderly patients: a pooled analysis of 21 randomized clinical trials with celecoxib and nonselective NSAIDs. Curr Med Res Opin. 2011;27(7):1359–66. 10.1185/03007995.2011.581274.
Sudano I, Flammer AJ, Roas S, Enseleit F, Noll G, Ruschitzka F. Nonsteroidal antiinflammatory drugs, acetaminophen, and hypertension. Curr Hypertens Rep. 2012;14(4):304–9. 10.1007/s11906-012-0274-7.
Sowers JR, White WB, Pitt B, Whelton A, Simon LS, Winer N, et al. The Effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus. Arch Intern Med. 2005;165(2):161–8. 10.1001/archinte.165.2.161.
Lewington S, Clarke R, Qizilbash N, Peto R, Collins R, Prospective Studies C. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360(9349):1903–13.
Ungprasert P, Srivali N, Thongprayoon C. Nonsteroidal anti-inflammatory drugs and risk of incident heart failure: a systematic review and meta-analysis of observational studies. Clin Cardiol. 2016;39(2):111–8. 10.1002/clc.22502.
Mamdani M, Juurlink DN, Lee DS, Rochon PA, Kopp A, Naglie G, et al. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet. 2004;363(9423):1751–6. 10.1016/S0140-6736(04)16299-5.
Nissen SE, Yeomans ND, Solomon DH, Luscher TF, Libby P, Husni ME, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016;375(26):2519–29. 10.1056/NEJMoa1611593.
Solomon DH, Husni ME, Wolski KE, Wisniewski LM, Borer JS, Graham DY, et al. Differences in safety of nonsteroidal antiinflammatory drugs in patients with osteoarthritis and patients with rheumatoid arthritis: a randomized clinical trial. Arthritis Rheumatol. 2018;70(4):537–46. 10.1002/art.40400.
Hirayama A, Tanahashi N, Daida H, Ishiguro N, Chachin M, Sugioka T, et al. Assessing the cardiovascular risk between celecoxib and nonselective nonsteroidal antiinflammatory drugs in patients with rheumatoid arthritis and osteoarthritis. Circ J. 2014;78(1):194–205.
Bruyere O, Cooper C, Pelletier JP, Branco J, Brandi ML, Guillemin F, et al. An algorithm recommendation for the management of knee osteoarthritis in Europe and internationally: a report from a task force of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Semin Arthritis Rheum. 2014;44(3):253–63. 10.1016/j.semarthrit.2014.05.014.